The purpose of this project is to establish a scientific basis for HTLV-associated transfusion-transmitted disease. In the area of HTLV-I-associated neurologic disease, we have been studying the effects of purified HTLV-I Tax protein on gene expression in NT2-N, post-mitotic cells that are remarkably similar to primary human neurons. Treatment of NT2-N with soluble Tax resulted in the synthesis of the cytokine TNF-alpha in a dose-dependent manner. Tax-induced TNF-alpha expression was relatively rapid, peaking within 6 hours of treatment. Remarkably, exposing NT2-N to Tax for as little as 5 minutes was sufficient to result in TNF-alpha production, indicating that the induction of TNF-alpha does not require Tax to be continually present. Given the toxicity of TNF-alpha for oligodendrocytes, the myelin-producing cells of the central nervous system, these results suggest that extracellular Tax may play a role in the demyelination observed in HAM/TSP through the induction of TNF-alpha in neurons. In another area, it has been observed that peripheral blood lymphocytes (PBL) from individuals infected with HTLV-II proliferate spontaneously in culture. We are examining this phenomenon, referred to as spontaneous lymphocyte proliferation (SLP), in a cohort of intravenous drug users (IVDU). We found that, whereas SLP was observed in cells derived from the majority of individuals infected with HTLV-II alone, SLP occurred significantly less frequently in PBL from HTLV-II+, HIV-1+ IVDU. These results suggest that HIV-1 infection negatively influences the ability of PBL to undergo SLP. Possible correlations with clinical observations in this population are being examined.